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The Role of Polyamines and Hypusine in Beta-Cell Dysfunction

Award Number: R01DK135832
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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The Role of Polyamines and Hypusine in Beta-Cell Dysfunction - PROJECT ABSTRACT There is a massive prevalence of diabetes in the U.S. with 34.2 million having diabetes, and 88 million adults with prediabetes. Type 1 diabetes results from the autoimmune destruction of the islet β cell mediated in part by β-cell dysfunction prior to autoimmune attack. Polyamine and hypusine production are important for the translation of a subset of RNAs involved in the unfolded protein response, ER stress, and cytokine response in the β cell. Our preliminary data suggests that the polyamine/hypusine pathway is involved in the translation of proteins required for the response of the β cell to inflammation. Inhibition of two rate limiting enzymes along the polyamine/hypusine pathway, either genetically or with small molecule inhibitors, results in a decrease of ER stress leading to protection from β-cell death and ultimately type 1 diabetes. For this proposal we will use a combination of mouse, and human models to understand how the polyamines and hypusine specifically alter the β cell’s response to stress. We propose to study the role of polyamines and hypusine in specific mRNA translation of proteins that are important to the maladaptive response of β-cell ER stress and hypothesis that polyamine depletion leads to ER stress resolution, preserved β-cell function, and ultimately reduced T1D pathogenesis. To test this hypothesis, we propose the following aims: Aim 1: Interrogate the molecular mechanisms by which the polyamine/hypusine pathway contributes to β-cell dysfunction and death. Aim 2: Determine the role of β cell polyamine/hypusine pathway during autoimmunity and the development of T1D. Aim 3: Assess the efficacy of treatment with polyamine/hypusine blockade. The primary impact of this proposal is the identification of mechanisms of the polyamine/hypusine pathway in β cells during the diabetes pathogenesis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $550,564 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/12/2025	NON-COMPETING CONTINUATION	$550,564
														Subtotal = $550,564

Issue Date FY: 2025 ( Subtotal = $547,710 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/12/2025	NON-COMPETING CONTINUATION	$54,770
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/18/2024	NON-COMPETING CONTINUATION	$492,940
														Subtotal = $547,710

Issue Date FY: 2024 ( Subtotal = $568,857 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/22/2023	NEW	$568,857
														Subtotal = $568,857

Grand Total All Awards = $1,667,131

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The Role of Polyamines and Hypusine in Beta-Cell Dysfunction

Award Number: R01DK135832

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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